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A selective and sensitive stability-indicating liquid chromatography tandem mass spectrometry (LC-MS/MS) method, operated in electrospray ionization (ESI) and quadrupole linear ion trap (QTRAP) mode, has been developed for the identification and structural characterization of stressed degradation products of indapamide. In this study, comprehensive...
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... chromatographic conditions were optimized to obtain high sensitivity, symmetric peak shape and short retention time for the analyte as shown in Fig. 2. The separation and ionization of the analyte were affected by the composition of the mobile phase. Several trials were preformed to test the elution type and ow rate, as well as the type of the chromatographic column in order to optimize the best chromatographic conditions. Gradient elution, in different mobile phase ratios with ...
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... In the tests section of the indapamide sustained-release tablets monograph of BP, two specific impurities are listed, namely 4-chloro-N-(2-methyl-1H-indol-1-yl) -3sulphamoyl-benzamide (Impurity B, denoted as ImB) and 4-chloro-3-sulfamoylbenzoic acid (denoted as Im1) which are tested at the test high performance liquid chromatography (HPLC) conditions [9] . In recent years, Kaddah [12] , Gumieniczek [13] , Pilard [14] and other research groups have studied the stability of indapamide under different conditions, such as heat and humidity, light, oxidation, acid-base, etc., referring to ICH Q1A (R2) and Q1B impurity research guidelines [7,8] , and obtained the possible degradation products. In order to avoid the potential danger of impurities in indapamide sustainedrelease tablets on patients with hypertension and guide the consistency evaluation of generic drugs, it is necessary to control the limits of the related impurities of generic indapamide sustained-release tablets, which has been seldom reported as we know. ...
The contents of indapamide and related impurities in generic indapamide sustained-release tablets were simultaneously detected by a single-run high performance liquid chromatography equipped with photodiode array detector (HPLC-PDA) method for the quality control in this paper. The results showed the method had a good selectivity and was validated through linearity, limits of detection and quantification, recovery, and precision. The linear ranges of indapamide, 2-methyl-1-nitroso-2,3-dihydro-1H-indole (impurity A, ImA), 4-chloro-N-(2-methyl-1H-indol-1-yl)-3-sulphamoyl-benzamide (impurity B, ImB) and 4-chloro-3-sulfamoylbenzoic acid (impurity 1, Im1) were 0.028-1.80 μg/mL (R=0.999 95), 0.060-1.20 μg/mL (R=0.999 6), 0.032 4-1.20 μg/mL (R=0.999 85) and 0.060-1.20 μg/mL (R=0.999 7) with detection limits of 0.009 3, 0.012, 0.012 and 0.006 μg/mL, respectively. ImA and Im1 were not detectable in the generic drug. The content of indapamide was 96.7% of the labeled amount with a relative standard deviation (RSD) of 1.30%, and the percentage of ImB relative to the labeled amounts of indapamide was 0.106% with an RSD of 1.82%. The content of other unspecified impurities all met the reference quality standards. The results provided references for the quality control and the quality standard study of generic indapamide sustained-release tablets.
... Structural characterization of the ZEN was performed using the information-dependent acquisition (IDA) method (Cao et al. 2017;He et al. 2018;Zeng et al. 2015;Zhou et al. 2018). The IDA method with dynamic background subtraction (DBS) was configured to trigger a sensitive enhanced product ion (EPI) scan when the survey scan signal exceeded the defined criteria (Attia et al. 2016;Lee et al. 2015;Xing et al. 2016). An EPI spectrum library was constructed and can be used for ZEN compound screening. ...
A simple, rapid, and efficient liquid chromatography tandem mass spectrometry (LC–MS/MS) method, operated in electrospray ionization (ESI) and quadrupole linear ion trap modes, has been developed for the identification and structural characterization of zearalenone (ZEN) in corn oil. Samples (5 g) were extracted with acetonitrile/water (80:20, v/v). After centrifugation and dilution, the extracts were separated on a C18 analytical column by gradient elution (acetonitrile/water) and analyzed by UPLC–MS/MS. The developed multiple reaction monitoring–information-dependent acquisition–enhanced product ion method enabled quantification and confirmation of the analyte in a single run. Enhanced product ion mode was used for qualitative analysis, while multiple reaction monitoring mode was used for quantitative analysis. An in-house library was constructed for identification. Calibration curve showed good linearity with correlation coefficients (r) higher than 0.995. Limit of detection was determined to be below 0.20 μg kg⁻¹ for ZEN. The recovery for ZEN was in the acceptable range of 86.6 to 97.2%. 82.4 % of the samples were found to contain ZEN among the 51 samples.
... Structural characterization of the ZEN was performed using the information-dependent acquisition (IDA) method [21][22][23][24] . The IDA method with dynamic background subtraction (DBS) was con gured to trigger a sensitive enhanced product ion (EPI) scan when the survey scan signal exceeded the de ned criteria [25][26][27] . ...
Background: A simple, rapid, and efficient liquid chromatography tandem mass spectrometry (LC–MS/MS) method, operated in electrospray ionization (ESI) and quadrupole linear ion trap modes, has been developed for the identification and structural characterization of zearalenone (ZEN) in corn oil.
Methods: Samples (5 g) were extracted with acetonitrile/water (80:20, v/v). After centrifugation and dilution, the extracts were separated on a C18 analytical column by gradient elution (acetonitrile/water) and analyzed by UPLC–MS/MS. Enhanced product ion mode was used for qualitative analysis, while multiple reaction monitoring mode was used for quantitative analysis.
Results: Calibration curve showed good linearity with correlation coefficients (r) higher than 0.995. Limit of detection was determined to be below 0.20 μg kg⁻¹ for ZEN. The recovery for ZEN was in the acceptable range of 86.6% to 97.2%. 82.4 % of the samples were found to contain ZEN among the 51 samples.
Conclusion: The sample pretreatment and LC–MS methods developed in this research, from a convenience and analysis time perspective, are simple, efficient, cheaper, and less time-consuming than existing methods.
... Structural characterization of the aflatoxins was performed using the information-dependent acquisition (IDA) method. [17][18][19][20] The IDA method with dynamic background subtraction (DBS) was configured to trigger a sensitive enhanced product ion (EPI) scan when the survey scan signal exceeded the defined criteria. [21][22][23] An EPI spectrum library was constructed and can be used for aflatoxin compound screening. ...
A simple, rapid, and efficient liquid chromatography tandem mass spectrometry (LC–MS/MS) method, operated in electrospray ionization and quadrupole linear ion trap modes, has been developed for the identification and structural characterization of aflatoxins in peanuts and its derivative products or bean sauce. Samples (5 g) were extracted with acetonitrile/water/formic acid (79:20:1, v/v). After centrifugation and dilution, the extracts were separated on a C18 analytical column by gradient elution (acetonitrile/0.2% formic acid) and analyzed by UPLC–MS/MS. External calibration was used for qualification. The developed multiple reaction monitoring–information-dependent acquisition–enhanced product ion method enabled quantification and confirmation of the analytes in a single run. Enhanced product ion mode was used for qualitative analysis, while multiple reaction monitoring mode was used for quantitative analysis. An in-house library was constructed for identification. Calibration curves showed good linearity with correlation coefficients (r) higher than 0.994. Limits of detection were determined to be below 0.26 µg kg ⁻¹ for most analytes. The recoveries for those substances were in the acceptable range of 80.2%–119.1%. A new LC–MS ³ method was established for further confirmation. One pickled pepper peanut was found to contain aflatoxins B1, B2, and G1 with contents of 90.93, 26.64, and 1.92 µg kg ⁻¹ , respectively.
... The degradation profiles of indapamide (4-chloro-N-(2-methyl-1-indoline-)-3-sulfamoylbenzamide), a well-known thiazide-like diuretic that is used in the treatment of hypertension [12], were studied in acidic, basic, and oxidative conditions to validate our workflow ( Figure 1). Concerning this API and its DPs (Table 1), a recent and well documented article [13] reported the analytical methods that are commonly used for their identification in different matrices (pharmaceutical formulations, biological fluids). They are mainly based on HPLC-UV and LC-ESI-MS/MS techniques (LC abbreviation, refer to HPLC or to UPLC). ...
... The main steps of our approach are based on an original sample preparation protocol, which leads to consistent MS and NMR information and the use of a pool of relevant MS and NMR experiments for qualitative and quantitative purposes. The degradation profiles of indapamide (4-chloro-N-(2-methyl-1-indoline-)-3-sulfamoylbenzamide), a well-known thiazide-like diuretic that Chemical structures, theoretical mass-to-charge ratios (m/z), 1 H and 13 C numbering of indapamide (API) and its main DPs (the nomenclature of the degradation products (DPs) was adapted from the publication of Kaddah's group [13], 4-chloro-N-(2-methyl-1H-indol-1-yl)-3-sulfamoylbenzamide (DP1) and 2-methyl-2,3-dihydro-1H-indol-1-amine (DP4) correspond, respectively, to Imp B and Imp C of the European Pharmacopeia, 9th edition [12]). 2-methyl-1H-indol-1-amine (DP2) and DP4 are only characterized by electrospray ionization source (ESI + ) and 4-chloro-3-sulfamoylbenzoate structure (DP3) by ESI − . is used in the treatment of hypertension [12], were studied in acidic, basic, and oxidative conditions to validate our workflow ( Figure 1). ...
... 2-methyl-1H-indol-1-amine (DP2) and DP4 are only characterized by electrospray ionization source (ESI + ) and 4-chloro-3-sulfamoylbenzoate structure (DP3) by ESI − . is used in the treatment of hypertension [12], were studied in acidic, basic, and oxidative conditions to validate our workflow ( Figure 1). Concerning this API and its DPs (Table 1), a recent and well documented article [13] reported the analytical methods that are commonly used for their identification in different matrices (pharmaceutical formulations, biological fluids). They are mainly based on HPLC-UV and LC-ESI-MS/MS techniques (LC abbreviation, refer to HPLC or to UPLC). ...
A global approach that is based on a combination of mass spectrometry (MS) and nuclear magnetic resonance (NMR) data has been developed for a complete and rapid understanding of drug degradation mixtures. We proposed a workflow based on a sample preparation protocol that is compatible to MS and NMR, the selection of the most appropriate experiments for each technique, and the implementation of prediction software and multivariable analysis method for a better interpretation and correlation of MS and NMR spectra. We have demonstrated the efficient quantification of the remaining active pharmaceutical ingredient (API). The unambiguous characterization of degradation products (DPs) was reached while using the potential of ion mobility-mass spectrometry (IM-MS) for fragment ions filtering (HDMSE) and the implementation of two-dimensional (2D) NMR experiments with the non-uniform sampling (NUS) method. We have demonstrated the potential of quantitative NMR (qNMR) for the estimation of low level DPs. Finally, in order to simultaneously monitor multi-samples, the contribution of partial least squares (PLS) regression was evaluated. Our methodology was tested on three indapamide forced degradation conditions (acidic, basic, and oxidative) and it could be easily transposed in the drug development field to assist in the interpretation of complex mixtures (stability studies, impurities profiling, and biotransformation screening).
... Ces dernières années ont vu l'émergence d'un nombre important de travaux montrant la performance du couplage CLHP-HRMS n dans la caractérisation des produits de dégradation de principes actifs dans un contexte pharmaceutique (Attia et al., 2016 ;Bhandi et al., 2016 ;Lei et al., 2017) ou environnemental (Segalin et al., 2015 ;An et al., 2015 ;. En effet, ce couplage permet, dans la plupart des cas, d'acquérir des données suffisamment caractéristiques pour établir la structure des substances apparentées au principe actif. ...
Au cours de son cycle de vie, le principe actif se retrouve en solution dans différentes situations : dans desformes pharmaceutiques liquides, dans l’organisme et dans les eaux usées. Or, par rapport à l’état solide, lamise en solution du principe actif l’expose davantage à des facteurs susceptibles de conduire à sa dégradation.Les transformations modifient sa structure chimique et donc potentiellement ses activités pharmacologiques ettoxicologiques.L’objectif de ce travail de thèse est de présenter une méthodologie et des études visant à prédire le devenir ensolution de principes actifs et les impacts potentiels consécutifs à leur dégradation.Trois principes actifs ont été sélectionnés pour la réalisation de ce travail. Ils ont en commun de présenter,d’une part, une activité pharmacologique élevée corrélée à une toxicité potentielle de leurs produits dedégradation et, d’autre part, l'absence de données sur leurs comportements en solution. Dans tous les cas,bien que le contexte soit singulier pour chaque molécule, l’approche méthodologique suivie intègre aussi biendes travaux expérimentaux que des études ab initio et in silico.La première étude porte sur le devenir de l’apixaban, principe actif actuellement commercialisé sous formeorale solide, en solution aqueuse. Les données expérimentales ont mis en évidence des groupementschimiques du principe actif pouvant contribuer à son instabilité. L’approche ab initio a permis d’expliquer larégio-spécificité de la réaction d’hydrolyse dépendamment du pH. À partir de la structure des produits dedégradation caractérisés, l’étude de leur potentiel toxique a été réalisée par approche in silico. Ces donnéesconcourent à la démarche d'analyse et évaluation des risques déployée lors de développements de formespharmaceutiques liquides ou des situations particulières impliquant la mise en solution de l'apixaban aumoment de l'administration.De telles approches ont également été employées pour caractériser les mécanismes de photodégradation del’argatroban et évaluer le potentiel toxique des produits de dégradation. Les processus initiant laphotodégradation ont fait l’objet d’études complémentaires reposant sur des calculs d’énergies. Cesconnaissances pourront apporter le rationnel nécessaire au choix de procédés capables de réduire laphotodégradation de l’argatroban et son impact sur les patients. Elles pourront également servir à anticiper lessituations d’écarts pouvant mettre en jeu le rapport bénéfice risque du médicament telles que le mésusage oula modification de la forme pharmaceutique administrée.Enfin, dans un contexte autre que le contexte pharmaceutique, une étude de dégradation du pémétrexed parphotocatalyse via un procédé d'oxydation avancée a été réalisée. Il s'agit d'un procédé particulièrement étudiépour sa capacité à réduire l’empreinte environnementale de composés organiques en accélérant leurdégradation. Le choix de ce principe actif utilisé comme anticancéreux a été justifié par son caractère toxiqueet rémanent dans les eaux de surface, ce qui en fait un produit à haut risque environnemental. Ce travail amontré que des produits de plus faible masse résultant de la transformation photocatalytique du pémétrexedsont malheureusement plus toxiques et encore plus rémanents que la molécule mère elle-même. Ces résultatscontribuent donc à souligner que les procédés d'oxydation avancée, bien qu'efficaces pour l'élimination despolluants médicamenteux, sont à évaluer au regard de l'existence d'un risque accru pour l'environnementavant toute perspective d'utilisation à grande échelle.Les approches et les résultats présentés dans cette thèse pourront être employés pour d’autres études visant àprédire, prévenir et réduire l’impact de la dégradation du principe actif sur le patient et l’environnement.
An understanding of drug product degradation issues is needed to advise stable formulation and provide a reasonable shelf‐life evaluation for all drug products. For this purpose, we have developed and validated a novel HPLC method for assessing the stability of vardenafil and dapoxetine in a combined pharmaceutical dosage form. The chromatographic separation was accomplished on a ProntoSIL C18 KROMA PLUS column (250×4.6 mm, 5 μm). The column was run under isocratic conditions with a 2.0 mL/min flow rate. The mobile phase was made up of methanol and 20 mM potassium dihydrogen phosphate at 45 : 55 (v/v), which was adjusted to pH 3.0 with phosphoric acid; these two drugs were eluted at retention times of 5.33 and 9.91 min for vardenafil and dapoxetine, respectively. The proposed method shows a linearity of 1–50 ug/ml with a regression of 0.9999 for both drugs. The method was validated for accuracy, precision, linearity, specificity, and sensitivity. The developed HPLC method has been successfully implemented to analyse dapoxetine and vardenafil in tablets. Furthermore, the stress degradation experiments were conducted on the bulk powder of vardenafil and dapoxetine following the International Council for Harmonization (ICH) recommendations.
Antimicrobial agents are essential to protect human and animal health. During the COVID‐19 pandemic, antimicrobials such as cephalosporins were widely used as prophylactics and to prevent bacterial co‐infection. Undoubtedly, the prevalence of antibiotics in the aquatic environment will ultimately affect the degree of resistance against these bacteria in animals and the environmental systems. In order to monitor sixteen cephalosporins in the aquatic environment, we developed a new LC‐MS/MS method that functioned simultaneously under positive and negative ESI switching modes. The chromatographic separation has been implemented using a pentafluorophenyl propyl column kept at 40°C. The limits of detection and quantitation for the studied cephalosporins ranged from (8 × 10−4) to (7.11 × 10−2) ng/mL and from (2.61 × 10−3) to (2.37 × 10−1) ng/mL, respectively. The percent extraction efficiency (apparent recovery) and relative standard deviations for the analyzed cephalosporins ranged from 61.69 to 167.67% and 2.45 to 13.48%, respectively. The overall findings showed that the effluent from the wastewater treatment plants that receive wastewater from pharmaceutical factories had a higher detected amount of cephalosporins than that of domestic sewage. Moreover, seven cephalosporins, including cefuroxime, ceftazidime, cefradine, cefprozil, cefixime, cefalexin, and cefadroxil (0.68–105.45 ng/L) were determined in the aquatic environment. This article is protected by copyright. All rights reserved
A fast, uncomplicated, sensitive, and fully validated high‐performance liquid chromatography‐tandem mass spectrometry (HPLC‐MS/MS) method has been developed for estimating L‐amino acids in the plasma of schizophrenic patients. The gradient‐elution chromatographic method was implemented with the Luna® PFP column (50 × 2.0 mm, 5‐μm), and a mobile phase of 0.1% formic acid in water and methanol was used. The intraday and interday variability of the L‐amino acids were less than 13.11%, and their accuracy ranged from 85.14 – 116.75% at the quality control levels and the lower limit of quantification (LLOQ) ranged from 2.5 – 15 nM. The extraction efficiency (apparent recovery) of amino acids from healthy plasma was employed by spiking the plasma with standard amino acids at the quality control levels. Their percentage recoveries ranged from 80.4% to 119.94%. Our method has a short run time and fast sample preparation compared with existing methods, which are suffered from long preparative steps and/or time‐consuming analysis, restricted reagents, and suboptimal performance characteristics presently available technologies. Therefore, the proposed HPLC‐MS/MS method was effectively applied for monitoring the L‐amino acids in the plasma of schizophrenic patients and healthy volunteers.
Bioassay-guided investigation of Panicum turgidum extract resulted in the identification of seven steroidal saponins (Turgidosterones 1-7). They were evaluated for their in vitro antifungal, antileishmanial, and antitrypanosomal activities. Turgidosterone 6 was the most active antifungal against Candida albicans and Candida neoformans (IC50 values of 2.84 and 1.08 μg mL-1, respectively). Turgidosterones 4-7 displayed antileishmanial activity against Leishmania donovani promastigotes with IC50 values ranging from 4.95 to 8.03 μg mL-1 and against Leishmania donovani amastigote/THP with IC50 values range of 4.50-9.29 μg mL-1. Activity against Trypanosoma brucei was also observed for Turgidosterones 4-7 with an IC50 values range of 1.26-3.77 μg mL-1. Turgidosterones 1-3 did not display any activity against the tested pathogens. The study of structure-activity relationships of the isolated saponins indicated that the antifungal, antileishmanial, and antitrypanosomal activities are markedly affected by the presence of spirostane-type saponins and the elongation of the sugar residue at C-3. To quantitatively determine the most abundant active ingredient in Panicum turgidum extract, a single run, sensitive, and highly selective liquid chromatography-tandem mass spectrometry (LC-MS/MS) method has been applied under positive and negative modes. The obtained results showed that compound 5 was the most abundant (95.93 ± 1.10 mg per gram of dry Panicum turgidum extract), followed by 6 (52.51 ± 1.05 mg gm-1), 4 (32.71 ± 0.48 mg gm-1), and 7 (13.19 ± 0.50 mg gm-1). Docking of these saponins against the Candida albicans oxidoreductases and Leishmania infantum trypanothione reductase active sites revealed their potential to effectively bind with a number of key residues in both receptor targets. This journal is
